There has been increasing interest in biologically active compounds known as α-Trifluoromethyl ketones (TFMKs). It has been found that many TFMK compounds have unique properties due to its α-trifluoromethyl ketone functionality. In example, TFMK's have been found to be potential hydrolytic enzyme inhibitors. In particular, TFMK's have been found to be inhibitors of protease.
Kawase has reported that the trifluoromethyl group in the α-position of the carbonyl of the TFMK facilitates the formation of tetrahedral hemiketals or hydrates with water. The hydrated molecule interacts with protease, and inhibits the enzyme activity Kawase, M. J. Syn. Org. Chem. Jpn. 2001, 59, 755, which is incorporated herein by reference thereto.
It has also been demonstrated that TFMK's are cytotoxic agents against human oral tumor cell lines, such as human squamous carcinoma cells HSC-2 and salivary gland tumor cells HSG. Kawase, M.; Sakagami, H.; Kusama, K, Motohashi, N.; Saito, S. Bioorg. Med. Chem. Lett. 1999, 9, 3113, incorporated herein by reference.
Traditionally, TFMKs are prepared from inexpensive trifluoroacetic acid derivatives. See, Creary, X. J. Org. Chem. 1987, 52, 5026; Keumi, T.; Shimada M.; Takahashi, M.; Kitajama, H. Chem. Lett. 1990, 783. Both of which are incorporated herein by reference. Additionally, the present inventors have recently reported the direct preparation of TFMKs from carboxylic esters with (trifluoromethyl)trimethylsilane (TMS-CF3). See, Wiedemann, J.; Heiner, T.; Mloston, G.; Prakash, G. K. S., Olah, G. A. Angew. Chem. Ant. Ed. 1998, 37, 820, which is incorporated herein by reference thereto.
Our reported method has been extended by others with CsF catalyzed trifluoromethylation of esters. Most recently we have developed a simple and convenient general synthesis of α-trifluoromethyl ketones by fluorination using elemental fluorine F2 (Prakash, G. K S.; Hu, J.; Alauddin, M. M.; Conti, P. S.; Olah, G. A. J Fluorine Chem. 2003, 121, 239, incorporated herein by reference thereto.
There is a need for an expedient process for radioactive labeling of TFMKs. However, the current synthesis methods are not suitable for the synthesis of [18F]-labeled TFMKs since it is difficult to prepare [18F]-labeled trifluoroacetic acid derivatives or TMS-CF3 due to the short half-life of 18F (t1/2=110 min).